Preparation of 1,4-substituted-imidazolin-2-ones

ABSTRACT

1,4-Substituted-imidazolin-2-ones optionally substituted in the 5 position are prepared from N-propenyl-carbamoyl azides by thermolysis. The compounds are useful as analgesics, antipyretics, anti-inflammatories, herbicides and as intermediates in the preparation of imidazolidinones by hydrogenation which can be hydrolyzed to diamines which are useful in producing polyamides.

United States Patent [191 Chupp [54] PREPARATION OF 1,4-SUBSTITUTED-IMIDAZOLIN-Z-ONES [75] Inventor: John P. Chupp, Kirkwood, Mo.

[73] Assignee: Monsanto Company, St. Louis, Mo.

[22] Filed: Apr. 22, 1971 [21] App1.No.: 136,611

[52] 11.8. C1 ..260/309.6, 260/295 L, 260/295 E, 260/349 51 Int. Cl...C07d 49 34 [58] Field of Search ..260/309.6

[56] References Cited UNITED STATES PATENTS 2,707,186 4/1955 Duschinsky...260/309.6 3,136,776 6/1964 Stoffel 260/309 6 Pesterfield....Pesterfield ..260/309.6

l l Mar. 27, 1973 3,629,279 12/1971 Pesterfield ..260/309.6

OTHER PUBLICATIONS Schipper et al. In: Elderfield Heterocyclic CompoundsVol. 5. Pages 246-247 N.Y., Wiley, 1957. QD400.E4

Primary ExaminerNata1ie Trousof Attorney-Neal E. Willis, Paul C. Krizovand William T. Black [57] ABSTRACT 9 Claims, No Drawings PREPARATION OF1,4-SUBSTITUTED- lMlDAZOLlN-2-0NES This invention relates to theproduction of 1,4-substitued-imidazoline-Z-ones and is more particularlyconcerned with the production of such compounds by the thermolysis ofcarbamoyl azides bearing an N-allyl or terminally substituted allylgrouping with concomitant double-bond isomerization.

The preparation of various imidazolin-2-one derivatives by use ofassorted catalytic methods is shown in the prior art. For example,Japanese Pat. No. 12,940, July 8, 1964 shows the preparation ofimidazolidinone derivatives by treating propargylurea with aconcentrated strong acid. There is also described in the literature aseries of imidazolinone derivatives prepared by treating varioussubstituted propynyl ureas with phosphorous pentachloride.

it is an object of the present invention to provide a rapid and cheapprocess for the synthesis of irnidazolin- 2-ones by cyclization ofN-substituted N-(Z-alken-l-yl) carbamoyl azides.

In accordance with the process of this invention, N- substitutedcarbamoyl azides of the formula wherein R is hydrogen or a monovalentorganic group selected from the class consisting of alkyl groupscontaining a maximum of 12 carbon atoms, cycloalkyl containing from fourto seven carbon atoms, alkenyl groups containing from two to 12 carbonatoms, cycloalkenyl containing from four to seven carbon atoms, aralkylgroups containing from seven to l7 carbon atoms, aryl groups containinga maximum of 12 carbon atoms, such aryl groups substituted with halogen,lower alkyl, lower alkoxy, lower alkoxyalkyl, or trifluoromethyl, andhalogen, and heterocyclic groups such as pyridyl, etc., R and R" areeach independently selected from the group consisting of hydrogen, alkylhaving from one to 12 carbon atoms, aralkyl, aryl containing from six to12 carbon atoms and alkenyl containing from two to 12 carbon atoms, areheated to temperatures of from about 40C to about 200C. to cause saidcarbamoyl azide to release nitrogen and to thermally rearrange toproduce an imidazolin-Z-one of the formula wherein R, R and R" areasabove defined.

Although a solvent is not necessary in the process of this invention, itis preferred to employ solvent in this process to provide ease ofhandling of the reactants and products, ease of reaction and high yieldof products. A solvent is also advantageously employed to dissipate theexothermic heat of reaction and to control the decomposition of theazides. Solvents which can be employed in the process of this inventionare those solvents having boiling points in the range of from 40C toabout 200C and in which the starting carbamoyl azides are soluble andwhich do not react with the azides. Such solvents are, for example,organic solvents, e.g., the chlorinated hydroaromatic hydrocarbons suchas chlorobenzene, dichlorobenzene, chlorotoluene, chloroxylene, and thehydrocarbyl solvents such as benzene, toluene, xylene, heptane,dodecane, decane, hexane, octane, undecane, etc., haloalkanes, e.g.,propyl chloride, butyl bromide, isobutyl chloride, etc. It is to beunderstood that this list is not exhaustive and many other suitablesolvents will be apparent to those skilled in the art.

The temperature at which the process of this invention is conducted isnot narrowly critical and can range from as low as 40C to as high as200C. It is preferred to employ temperatures in the range of to C in theprocess of this invention. Such temperatures are easily reached byemploying a solvent such as chlorobenzene or xylene in the process ofthis reaction and employing these solvents under reflux conditions.

Illustrative of the monovalent organic groups represented by R, R and R"are, for example, alkyl groups such as methyl, ethyl, propyl, isopropyl,n-hexyl, n-octyl, n-dodecyl, etc.; alkenyl groups such as vinyl, allyl,methallyl, butenyl, hexenyl, decenyl, dodecynyl, etc.; cycloalkyl groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc.; aralkyl groups such as benzyl, phenylethyl, phenylpropyl, etc.;aryl groups such as phenyl, naphthyl, tolyl, xyllyl, and such arylgroups containing from one to three of the following ring substituents:Halogens such as fluorine, chlorine or bromine; trifluoromethyl; loweralkyl; e.g., methyl, ethyl, propyl, butyl, hexyl, etc., lower alkenyl;e.g., vinyl, allyl, butenyl, etc., lower alkoxyalkyl; e.g.,methoxymethyl, ethoxyethyl, methoxypropyl, etc., lower alkoxy, such asmethoxy, ethoxy, etc., and heterocyclic groups such as pyridyl,pyridinyl, pyrrolidinyl, etc.

The carbamoyl halides employed in the preparation of the azide startingmaterials for the process of this invention are prepared by reacting thecorresponding amine or N-hydrocarbyl-N-alkylidene amine with phosgene ina benzene solvent, as shown in the following procedure usingN-methyl-N-cyclohexylidene amine as an example.

N-methyl-N-cyclohexylidene amine (N-methylimine from cyclohexanone)(0.22 moles) dissolved in benzene was added dropwise to a 12.5 percentsolution of phosgene in benzene which contained 25 grams of phosgene.After the imine had been added, the solution was refluxed for 1% hours,cooled, and the reaction mixture filtered. The filtrate was vacuumtreated to remove the solvent, and the residue distilled to give N-methyl-N-(l-cyclohexen-l-yl) carbamoyl chloride in a 62 percent yield.

The starting azides were then prepared by reacting the carbamoylchlorides with sodium azide in 80 percent aqueous acetone in accordancewith the following procedure showing the production of N-methyl-N-(lcyclohexen-l-yl) carbamoyl azide as an example.

Sodium azide (33 grams) was mixed with 275 ml of 80 percent aqueousacetone (20 percent water by volume) and 30 grams ofN-methyl-N-(l-cyclohexen l-y carbamoyl chloride added while maintaininga temperature below 30C. Material was stirred for 18 hours, the solutionfiltered and the material vacuum treated at room temperature. Theresidue was dissolved in ether, washed with water and dried overanhydrous magnesium sulfate. The ether solution was filtered and theether removed by vacuum evaporation near room temperature to yield theazide as a residue.

Preparation of carbamoyl azides not possessing a lcyclohexen-l-yl moietywas carried out with sodium azide in refluxing aqueous acetone.

The starting N-l-alkenyl-carbamoyl chlorides can also be prepared inaccordance with the procedure set forth in Belgian Pat. No. 744,409 byreacting Schiffs bases with phosgene. The carbamoyl chlorides can thenbe reacted with sodium azide to form carbamoyl azide starting materialfor the process of this invention.

The substituted imidazolin-Z-ones produced in accordance with thisinvention find uses as analgesics, anpy etics, anti-inflammatories,herbicides and as intermediates in the preparation of imidazolidinone bycatalytic hydrogenation employing hydrogen at 60 psig and a platinumoxide catalyst. The imidazolidinones are readily hydrolyzed to diamines(see U. S. Pat. No. 2,5 14,380) which are useful in the production ofpolyurethanes, polyamides and the like.

The following examples serve to further illustrate this invention. Allparts are parts by weight unless otherwise expressly set forth.

EXAMPLE 1 N-alyl-N-(l-cyclohexen-l-yl)carbamoyl azide (9.0 grams, 0.0445mole) was refluxed in chlorobenzene for 5 hours. The chlorobenzene wasremoved by vacuum evaporation and a residue was obtained which was shownby nuclear magnetic resonance spectral analysis to consist of about 20percent 1-allyl-4,5,6,7- tetrahydro-3-indazolinone and 80 percentl-(lcyclohexen-l-yl)-4-methyl-4-imidazolin-2-one. This residue wastreated with about 500 ml of boiling ether. The ether solution wasdecanted and evaporated to give a solid that was recrystallized fromethyl acetate yield-ing crystals having a melting point of l07-l08C.These crystals were identified as l-allyl-4,5,6,7-tetrahydro-3-indazolinone. The ether insoluble material wasrecrystallized from acetonitrile to give 3.8 grams of crystals (m.p.l56l6lC) which were identified as l-( l-cyclohexenl -yl)-4-methyl-4-imidazolin-2-one by nuclear magnetic resonance spectralanalysis, infrared spectral analysis and elemental analysis.

EXAMPLE 2 N-allyl-N-phenylcarbamoyl azide (5 grams, 0.025 mole) preparedin the general manner set forth above was heated in chlorobenzene atreflux temperature for 2 hours. The chlorobenzene was evaporated and theresidue, a semi-solid, was triturated with ether to give 2.4 grams of asolid (m.p. 170C). This solid was recrystallized from acetonitrile togive crystals which were identified asl-phenyl-4-methyl-4-imidazoline-2- one by infrared and nuclear magneticresonance spectral analysis and by elemental analysis.

EXAMPLE 3 Diallylcarbamoyl chloride (16 grams, 0.10 mole) was placed in100 ml of percent aqueous acetone with 13 grams of sodium azide. Afterrefluxing for 3 hours, the material was cooled, filtered, and thefiltrate vacuum treated to remove most of the acetone. The residue wastaken up in ether, washed twice with water and the ether solution driedover magnesium sulfate. The solution was then filtered and the etherevaporated off under vacuum at room temperature, yielding 12.4 grams ofa residue which was identified as N,N-diallyl carbamoyl azide. TheN,N-diallyl carbamoyl azide, 1 1.8 grams) was heated in chlorobenzene atreflux for 3 hours. The chlorobenzene was removed by vacuum evaporationleaving a residual oil which solidified on scratching the vessel with astirring rod. The solid was triturated with ether to give 7.5 gramscrystals (m.p. l00l05) which were identified as l-allyl-4-methyl-4-imidazolin-2-one by infrared, nuclear magnetic resonance spectralanalysis and elemental analysis.

EXAMPLE 4 N-Cinnamyl-N-methylcarbamoyl azide (4.6 g, 0.0213 mole) washeated at reflux in chlorobenzene for 3 hours. The chlorobenzene wasremoved by vacuum evaporation and the residue recrystallized from ethylacetate to give 1.4 grams of crystals (m.p. l59l 60C) which wereidentified as 1-methyl-4-benzyl-4- imidazoline-Z-one by infrared andnuclear magnetic resonance spectral analysis and elemental analysis.

Following the procedure of the previous example, the following azideswere decomposed into the corresponding imidazolin-2-ones:

N-allyl-N-benzyl carbamoyl azide to l-benzyl4-methyl-4- imidazolin-2-one(m.p. l62l65 C.) N-allyl- -(3 4-dichlorophenyl Carbamoyl azide tol-(3,4-

dichlorophenyl)-4- methyl-4- imidazolin-Z-onc (m.p. l76l78 C)N-allyl-N-(2,4-dichlorobcnzyl) carbamoyl azide to l-(2,4-

dichlorobcnzyl )-4- methyl-4- imidazolin-Z-onc (m.p. l76l78 C)N-allyl-N-pchlorobenzyl carbamoyl azide to l-p-chlorobenzyl-4- methyl-4-imidazolin-Z-one (m.p. 97-l24 C) N-allyl-N-( 2,6-dichlorobenzyl)carbamoyl azide to l-(2,6-

dichlorobenzyl)-4- methyl-4- imidazolin-2-one (m.p. 2l0-2l6 C)N-allyl-N-(Z-phenylethyl) carbamoyl azide to l-(2-phenylethyl)-4-methyl-4- imidazolin-Z-one (m.p. l02-l05 C) N-allyl-N-(3-chloro'4-tolyl)imidazolin-2-one N-allyl-N-(4-methyll cyclohexenl-yl)carbamoyl azidel-(4-methyll -cyclohexenl -yl)-4- methyl-4- imidazolin-2-one (m.p. l28l35 C) What is claimed is: 1. A process for the preparation of animidazo-lin-Z- one of the formula wherein R is alkyl of from one to 12carbon atoms, cycloalkyl of from four to seven carbon atoms, alkenyl offrom two to 12 carbon atoms, cycloalkenyl of six carbon atoms,cycloalkenyl of six carbon atoms substituted with lower alkyl, phenyl,phenyl lower alkyl and phenyl or phenyl lower alkyl wherein the phenylgroup is substituted with from one to three substituents selected fromthe group consisting of halogen, lower alkyl and low alkoxy; R and R"are each independently hydrogen, lower alkyl or phenyl; which comprisesheating an encarbamoyl azide of the formula wherein R, R and R" are aspreviously defined, in a solvent in which said encarbamoyl azide issoluble and which is not reactive therewith, to a temperaturesufficiently elevated so as to cause said encarbamoyl azide todecompose, thereby forming said irnidazoline-Z-one.

2. The process of claim 1 wherein the temperature is from 40C to about200C.

3. The process as in claim 1 wherein the temperature is from C to aboutC.

4. The process of claim 1 wherein the solvent 18 chlorobenzene.

5. The process of claim 4 wherein the encarbamoyl azide is N-allyl-N-(l-cyclo-hexen-l-yl) carbamoyl azide.

6. The process of claim 4 wherein the encarbamoyl azide inN-cinnamoyl-N-methylcarbamoyl azide.

7. The process of claim 4 wherein the encarbamoyl azide isN-allyl-N-phenylcarbamoyl azide.

8. The process of claim 4 wherein the encarbamoyl azide isN-diallylcarbamoyl azide.

9. The process of claim 4 wherein the encarbamoyl azide isN-allyl-N-(3,4-dichlorophenyl)carbamoyl azide.

2. The process of claim 1 wherein the temperature is from 40*C to about200*C.
 3. The process as in claim 1 wherein the temperature is from100*C to about 150*C.
 4. The process of claim 1 wherein the solvent ischlorobenzene.
 5. The process of claim 4 wherein the encarbamoyL azideis N-allyl-N-(1-cyclo-hexen-1-yl) carbamoyl azide.
 6. The process ofclaim 4 wherein the encarbamoyl azide in N-cinnamoyl-N-methylcarbamoylazide.
 7. The process of claim 4 wherein the encarbamoyl azide isN-allyl-N-phenylcarbamoyl azide.
 8. The process of claim 4 wherein theencarbamoyl azide is N-diallylcarbamoyl azide.
 9. The process of claim 4wherein the encarbamoyl azide is N-allyl-N-(3,4-dichlorophenyl)carbamoylazide.